ELEVEN SAAS SEED GRANTS HAVE BEEN AWARDED
The Stanford Autoimmune & Allergy Supergroup (SAAS) is pleased to announce that it has funded eleven highly collaborative and interdisciplinary proposals in the fields of allergies or autoimmune diseases Here are the list of winners and abstracts:
1. Jeong Hyun, MD, Peds, Co-Investigator: Michael T. Longaker, Deane and Louise Mitchell Professor, Medicine, Department of Surgery, Co-Investigator: Alka Goyal, Clinical Professor, Department of Gastroenterology, Pediatric Gastroenterology and IBD Specialty
Surgery Characterization of Mesenteric Fibrosis in Creeping Fat in Crohn’s Disease Creeping fat is pathognomonic for Crohn’s disease but it’s role in the development of this disease process is poorly understood. Recent research has shown that fat is an important modulator for inflammation. Surgeons have long used creeping fat to mark the extent of their resection in Crohn’s disease patients. We seek to understand the role that creeping fat plays in the development of stricture formation in Crohn’s disease. Our hypothesis is that fibroblasts derived from the creeping fat are key mediators in this autoimmune process and our research aims to identify these cells and characterize them in order to better understand Crohn’s disease pathogenesis and optimize future treatment.
Mignot, MD, PhD, Mark M. Davis, PhD, Director, ITI, Professor, M&I, Holden
T. Maecker, PhD, Director, HIMC, Professor, M&I, Xuhuai Ji, MD, PhD, HIMC,
Guo Lo, PhD, Instructor, Mignot Lab
Anti-IgLON5 disease: autoimmunity meets neurodegeneration Anti-IgLON5 disease is an uncommon autoimmune encephalitis characterized by antibodies against the cell adhesion protein IgLON5 and a localized tauopathy with preferential involvement of the brainstem. Age of onset is usually above 60 years, both sexes are equally affected, and manifestations are heterogeneous and often resembling neurodegenerative disorders. Moreover, there is strong evidence supporting that anti-IgLON5 disease has a particular combination of autoimmune and neurodegenerative features. On the one hand, neuropathological studies revealed accumulation of hyperphosphorylated tau protein predominantly in the brainstem, together with neuronal loss and gliosis. Furthermore, stem cell-based in vitro models showed neurodegenerative changes, including increased cell death and ptau accumulation when exposed to IgLON5 antibodies. This suggests that antibodies may disrupt the cytoskeleton, leading to ptau accumulation and neuronal death. On the other hand, anti-IgLON5 disease is ~70% associated with human leukocyte antigen (HLA) DQ5, which along with the presence of autoantibodies, supports autoimmunity as a primary cause. Improved understanding of this relationship will likely allow for more specific and effective therapies, especially since current approaches are often unsuccessful. The aim of our project is to improve our understanding of pathophysiological, autoimmune and neurodegenerative mechanisms involved in anti-IgLON5 disease through the study of its genetic (HLA) predisposition and phenotyping anti-IgLON5 DQ5-restricted T cells.
Krams, PhD, Senior Associate Dean for Graduation for Graduate Education and
Postdoctoral Affairs, Carlos Esquivel, MD, PhD, Transplantation &
Characterization of a CD4+ T Cell Population Associated with “Tolerance Solid organ transplant is lifesaving treatment for children with end-stage heart, liver, or kidney disease. Protection of the transplanted organ from rejection requires drugs which suppress the recipient’s immune system. Although these agents provide protection to the allograft, the recipient is vulnerable to complications including infection and malignancy. An emerging paradigm for more specific immunomodulation involves harnessing the intrinsic regulatory capacity of the immune system. Tregs are a subset of CD4+ cells that dampen the immune response to both self- and non-self-antigens, often in an antigen-specific manner. We previously identified a subpopulation of CD4+ T cells that were increased in abundance in a small cohort of operationally tolerant pediatric liver transplant recipients; this subset of CD4+ T cells was termed “T cells of Operational Tolerance” or TOT cells. Recently, we constructed immune profiles from the peripheral blood of 52 pediatric transplant recipients enrolled in the multi-center Clinical Trials in Organ Transplantation in Children (CTOT-C) 06 study and demonstrated that TOT cells were less abundant in the 30-day period leading up to an episode of rejection. TOT cells were decreased not only in pediatric liver recipients but also children who received heart and kidney allografts. We hypothesize that TOT cells represent a novel, intermediate T cell subset that may act as a “ready reserve” of T cells that can be shuttled towards a Treg phenotype. In this proposal, we propose three specific aims: Aim 1: Define the phenotype, transcriptional signatures, and cytokine profile of TOT cells in transplant recipients, Aim 2: Determine whether TOT cells have immunomodulatory activity, and Aim 3: Establish if TOT cells are decreased prior to rejection. These experiments, using primarily samples already stored in our lab, will define the phenotype and function of TOT cells, and determine If TOT cells can be harnessed to predict or prevent allograft rejection.
Horomanski, MD, Clinical Asst Prof, Rheum, Julia Simard, ScD, Epidemiology,
Gary M. Shaw, DrPH, Pediatrics
A US national-scale investigation of pregnancy risks associated with systemic vasculitis Systemic vasculitides are rare rheumatic disorders characterized by vascular inflammation leading to stenosis, aneurysm, and infarction. Although the spectrum of disease manifestations varies by the type of vasculitis, the vascular injury can affect virtually every organ system. The aggressive and multisystem nature of these disorders has been associated with high morbidity and mortality, but recent treatment advances have increased life expectancy and decreased toxicity, allowing more patients the opportunity to pursue pregnancy. However, due to the rarity of these disorders, little is known about the maternal and fetal risks associated with pregnancy and delivery. Small studies have shown an increased risk of preeclampsia, preterm delivery, and intrauterine growth retardation, but more data are needed to guide clinical monitoring and prognostication. As pregnancies in patients with vasculitis remain rare events, analysis of large datasets is needed to provide meaningful conclusions. Our experienced interdisciplinary group from Pediatrics, Epidemiology, Immunology and Rheumatology proposes to use IBM® MarketScan®, a national database of >250 million patients with integrated prescription data to expand our understanding of the risks of pregnancy in vasculitis patients. The aims of this project are to determine the risk of several adverse outcomes of pregnancy in patients with vasculitis, including various indications for preterm delivery and hypertensive disorders of pregnancy. We will also investigate the risk of vasculitis and pregnancy-related complications during the delivery hospitalization and the postpartum period. The knowledge gained from this project will address significant gaps in understanding and improve our ability to care for and support patients with vasculitis who pursue pregnancy.
Meffre, PhD, Medicine, Immunology & Rheum, Lorinda Chung, M.D., M.S.,
Immuno & Rheum, Sally Arai, MD, BMT
Correcting defective TLR9 function and impaired central B cell tolerance in systemic sclerosis. The goal of the proposed research is to determine whether blocking integrin alphaVbeta3 prevents CXCL4-mediated TLR9 inhibition in human B cells. Our working hypothesis is that interfering with CXCL4 binding to integrin alphaVbeta3 will restore impaired TLR9 function in B cells from patients with SSc and prevent the production of autoreactive B cells in humanized mice engrafted with hematopoietic stem cells isolated from SSc patients undergoing autologous bone marrow transplant. Blocking integrin alphaVbeta3 may therefore represent a novel therapeutic strategy that restores both impaired TLR9 function and central B cell tolerance in SSc and potentially other autoimmune diseases such as SLE in which TLR9 function in B cell is also defective. Obtaining data supporting this scenario will allow us to submit a patent to repurpose anti-integrin alphaVbeta3 etaracizumab (MEDI-522; trade name Abegrin), a humanized higher affinity variant derived from murine antibody LM609 developed by Medimmune and VPI-2690B from Janssen that have initially been developed to treat cancer and which have already been shown to be safe in phase I studies.
Rogers, MD, Medicine, Pulmonary, Allergy, and Critical Care Medicine, PJ Utz,
MD, Medicine, Rheumatology, Sam Yang, MD, Emergency Medicine
Inflammation and Auto-immunity in COVID-19 The overarching goal of our studies is to characterize autoantibodies (AAb) in COVID-19, focusing on their inflammatory capacity and abnormal regulation of B cell tolerance during infection. The pathogenic roles of AAb in COVID-19 are now widely recognized with Anti-Cytokine Antibodies (ACA) targeting type I interferons (IFN) identified in ~10% of critically ill patients, and rare in those with milder disease. We and others have also extended these findings to show the presence of IgG autoantibodies for a broad array of targets including Connective Tissue Disease (CTD) antigens and other cytokines in numerous COVID-19 cohorts. We have further found that more than half of patients in our non-COVID-19 cohorts have evidence of at least one AAb, suggesting that this loss of tolerance is applicable to infections beyond COVID-19. The clinical correlates between loss of tolerance characterized by auto-antibody formation and inflammation is largely unexplored and is the focus of this proposed work. Utilizing the outstanding resources of the Stanford COVID-19 biobank and immune phenotyping by Stanford’s HIMC, we will evaluate whether the plasma inflammatory environment differs in patients who exhibit loss of tolerance and AAb formation in the setting of infection. Importantly, this proposal also lays the groundwork for future grants exploring B cell functionality in patients with AAb, as PBMC are available for >90% of Stanford COVID-19 biobank patients, and both Olink and AAb data will be shared with Stanford investigators to be a resource to other ITI scientists.
Kuo, MD, PhD, Hematology, Seung Kim, MD, PhD, Dev Biology
Human islet organoid assays to investigate auto- and alloimmunity Autoimmune type 1 diabetes mellitus (T1D) arises from of loss of islet β cells, with substantial morbidity and mortality from neuropathy, nephropathy, retinopathy, and cardiovascular events. Synthetic insulins, pump and continuous glucose monitoring have greatly improved T1D patient outcomes, but do not tightly control glucose levels. Alternatively, islet and stem cell transplantation represent potential 'cures' for T1D, but the requirement for lifelong immunosuppression has prevented widespread adoption. Overall, new models and assays of human islet and immune cell interactions are urgently needed. Here, the Calvin Kuo and Seung Kim groups collaboratively develop novel in vitro and in vivo organoid models of human islet allo- and auto-immunity. In Aim 1, we validate novel organoid methods to grow human islets en bloc with stromal cells and tissue-resident immune cells without artificial reconstitution. These holistic islet organoids will be combined with allogeneic and autologous PBMC to establish models for rejection and tolerance, as a prelude to mechanistic studies, drug screening and to culturing biopsies from transplanted islets undergoing active rejection. Findings from Aim 1 can be modeled by gain- or loss-of-function systems derived from Aim 2, which establishes mouse models of transplant NSG-MHC I/II double knockout (NSG-DKO) mice with human hematopoietic stem cells (HSCs) and human islets. Paralleling Aim 1, we will assess (1) self-tolerance after transplantation of HLA matched HSCs and islets, and test for (2) allo-rejection after transplantation of HLA mismatched HSCs and islets, with eventual generation of in vitro organoid models from these mice. Overall, we present a comprehensive organoid-based approach to modeling human islet allo- and auto-immunity that leverages synergistic strengths of the Kuo and Kim labs, with application to pathogenesis and treatment.
Grazia Roncarolo, MD, Stem Cel Regenerative Medicine, Mark M. Davis, PhD,
Director, ITI, Professor, M&I, Alma-Martina Cepika, MD, PhD, Pediatrics,
The role of type 1 regulatory T (Tr1) cells in transplantation tolerance Type 1 regulatory T (Tr1) cells are an inducible, FOXP3-independent subtype of regulatory T cells. Tr1 cells are im-portant for maintenance of peripheral tolerance. Frequency of circulating Tr1 cells correlates with the induction of tolerance after allogeneic hematopoietic stem cell transplantation (HSCT), when the patient and stem cell donor are HLA-mismatched. In murine models of allogeneic HSCT, adoptive transfer of Tr1 cells induces transplantation tolerance. Allogeneic HSCT is often lifesaving for patients with high-risk leukemias, genetic diseases affecting hematopoietic stem cells, and refractory autoimmunity. However, HLA differences between the donor and the patient also increase the risk of potentially lethal graft-vs-host disease (GvHD), where alloreactive donor effector T cells (Teff) attacking patient’s healthy tissues. Tr1 cells are allospecific, i.e., they suppress alloreactive Teff cells without impairing Teff cell-mediated immune responses against tumors and pathogens. This allospecificity makes Tr1 cells a uniquely beneficial add-on therapy to HSCT. We are conducting a clinical trial where Tr1 cells and unmanipulated, allogeneic HSCT are administered to children and young adults with high-risk leukemias. Encouragingly, the first four patients are alive and well for more than a year post-treatment. However, first two patients experienced transient GvHD early after treatment, despite higher-than-normal level of Tr1 cells in their blood. GvHD could have occurred because infused Tr1 cells may have been transiently unstable in one or both of their two key properties required for suppression of alloreactive Teff cells: allospecificity and suppressive capacity. Here, we will test this hypothesis by measuring those key properties in patient peripheral blood Tr1 cells during transient GvHD, and after/without GvHD. Understanding Tr1 biology in patients receiving Tr1 cell therapy will enable us to elucidate the mechanism of transplantation tolerance and gain insight into the mechanism of allergy and autoimmune diseases.
Wheeler,MD, Cardiovascular, Holden T. Maecker, PhD, Director, HIMC, Jason Hom, MD, Medicine, Hospitalist, Alma-Maria
Cepika, Md, PhD, Pediatrics, Hematology, Oncology
Integrated multi-omics approach to diagnose and elucidate mechanisms of rare and undiagnosed Inborn Errors of Immunity. Inborn Errors of Immunity (IEI) are monogenic disorders that affect approximately 1 in 1,000 to 1 in 5,000 people, and can lead to a variety of immune disorders. In the recent past targeted gene panels, exome sequencing (ES) and genome sequencing (GS) have enabled diagnosis of numerous IEI. However, many candidate variants identified by sequencing are i) speculative Variants of Uncertain Significance (VUS) in IEI genes, or ii) are present in novel genes, not previously associated with IEI, or iii) lie in non-coding regions that are difficult to interpret. Moreover, even after a definitive clinical or genomic diagnosis, often little is understood about the cellular and molecular mechanisms of these orphan diseases, which hinders drug development and drug repurposing. Here, we propose to use bulk and single-cell transcriptomics and advanced algorithms to prioritize VUSs and non-coding variants for identifying the causative mutations in rare IEI disorders. We aim to provide evidence for the cellular and molecular mechanisms of these rare disorders using high dimensional single cell assays (mass cytometry and phospho-CyTOF), antibody based assays (multiplex cytokine luminex array and highly parallel serum epitope repertoire analysis technology) and publicly available data. The proposed research will help to facilitate accurate diagnosis of rare IEI disorders that will likely result in better management of the disease, identification of potential therapeutics, and avoid unnecessary treatments that may have severe side effects, inform the patient about their risk of passing the disease to future generations and help them evaluate alternate family planning options. Use of single cell technologies (single cell RNA-seq to cover a broader range of immune cells and CyTOF to distinguish the specific populations in more depth) will enhance our existing knowledge about the cellular and molecular biology of various under-studied IEI disorders. We expect that our integrated, multi-omics approach will provide a workflow to guide diagnosis of IEI patients with non-diagnostic ES or GS.
Snyder, PhD, Genetics, Kari Nadeau, MD, PhD, Medicine, Pediatric Food Allergy,
Immunology and Asthma, Chris Armstrong, U of Melbourne, ME/CFS, Linda Lan, PhD,
Genetics, Jaime Seltzer, Scientific and Medical Outreach, Arshdeep Chauhan,
Clinical coordinator, Genetics Department
Longitudinal Analyses of Long COVID, ME/CFS and PTLDS Using Wearable Devices and Microsampling Long COVID, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Post-Treatment Lyme Disease Syndrome (PTLDS) are known for chronic disability as post infection sequelae and represent a substantial healthcare burden. They have overlap in clinical features in addition to features of autoimmune illnesses, thereby suggesting the potential involvement of a common etiopathogenesis. To understand the underline causes and identify biomarkers that correlate to symptoms, we propose using wearable technologies and micro-sampling devices to enable real-time, continuous measurement of a wide range of biometrics. Through longitudinal integration of wearable outputs, surveys, and multi-omics data, we hope to reveal potential shared pathological pathways, the diagnostic markers, and therapeutic options. Through innovative approaches, the study aims to serve as a blueprint for studying other long haul diseases that may share similar symptom presentations and/or characteristics.
Mellins, MD, Jennifer Frankovich, MD, Allergy, Immunology and Rheumatology,
PANS Program Director, Alex Urban, PhD, Genomics, Hannes Vogel, MD, Pathology
The Blood Brain Barrier in PANS: regulatory mechanisms. Pediatric acute neuropsychiatric syndrome (PANS) is an abrupt-onset, relapsing-remitting neuropsychiatric disorder, characterized by obsessive-compulsive symptoms and/or eating restriction, sleep dysregulation, cognitive and behavior regression. Several lines of evidence suggest that blood brain barrier (BBB) integrity is reduced during flares of PANS. For example, autoantibodies to cholinergic interneurons in the caudate are implicated in active PANS, and antibody access to brain tissue requires a leaky BBB. Our preliminary data demonstrates involvement of two novel regulators of BBB in the context of PANS: C4 anaphylatoxin, an activation product of complement 4 protein that reduces BBB integrity, and alpha 7 nicotinic acetylcholine receptor, which helps maintain BBB integrity. PANS sera harbors C4 ana and exposure of brain endothelial cells (BEC) to PANS plasma reduces BBB integrity; an alpha 7 receptor agonist ameliorates the PANS plasma effect. In this project, we will investigate the mechanisms underlying these changes using a simple BBB model (human BEC monolayer) and a more complex model, the Emulate brain-on-a-chip, which includes endothelial cells, pericytes, microglia, astrocytes and neurons. Our approaches include confocal microscopy, transcriptional profiling, and proteomic analyses. We aim to reveal novel pathways that regulate BBB integrity, with possible therapeutic implications.